Cardiovascular Drugs and Therapy

, Volume 13, Issue 2, pp 115–122 | Cite as

Mibefradil, a T-Type and L-Type Calcium Channel Blocker, Limits Infarct Size through a Glibenclamide-Sensitive Mechanism

  • Michaela M. Mocanu
  • Shashi Gadgil
  • Derek M. Yellon
  • Gary F. Baxter


Summary. Mibefradil is a novel calcium channel blocker with activity at both L-type and T-type calcium channels. There are data suggesting that this compound can protect the ischemic/reperfused myocardium in spite of the fact that there is a very low abundance of T-type calcium channels within ventricular tissue. The aims of this study were twofold. First, we wished to study the protective effect of mibefradil on ischemia/reperfusion injury in the isolated rat heart using infarct size as the endpoint of injury. In this respect, we compared mibefradil with amlodipine, a well-known and potent L-type calcium channel blocker, and with ischemic preconditioning, an intervention known to reduce infarct size consistently. Secondly, we investigated the possible mechanisms through which protection was achieved. For this second purpose, we examined the effects on protection of glibenclamide (an ATP-dependent K+ channel blocker) and chelerythrine (a protein kinase C inhibitor). Isolated rat hearts were perfused in the Langendorff mode at constant pressure. Control, mibefradil-treated (0.3 µM), mibefradil plus glibenclamide (50 µM), and mibefradil plus chelerythrine (10 µM) treated hearts underwent 35 minutes regional ischemia followed by 120 minutes reperfusion. At the end of the experiments, infarct size was determined with triphenyltetrazolium chloride and was expressed as a percentage of the ischemic risk zone (I/R %). A significant reduction in infarct size with mibefradil treatment was observed (I/R 11.1 ± 2.1% vs. 35.5 ± 3.1% in controls). This was comparable with the infarct reduction seen with two 5-minute cycles of ischemic preconditioning (17.7 ± 2.5%). Amlodipine 0.1 µM, a concentration that caused equivalent coronary vasodilatation as that produced by mibefradil treatment, had no significant effect on infarct size (I/R 29.7 ± 3.5%). The protective effect of mibefradil was not significantly modified by the presence of the PKC inhibitor chelerythrine 10 µM (I/R 19.1 ± 4.9%) but was abolished when glibenclamide 50 µM was coadministered with mibefradil prior to ischemia (I/R 28.1 ± 4.7%). Neither chlelerythrine nor glibenclamide alone had any influence on infarct size. We conclude from these data that mibefradil, unlike amlodipine, markedly reduces infarct size in the rat isolated heart. This protection is sensitive to inhibition by glibenclamide, suggesting that KATP channel opening may be an important additional and novel mechanism of mibefradil's action.

mibefradil amlodipine ischemic preconditioning KATP protein kinase C glibenclamide chelerythrine myocardium infarct size 


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  1. 1.
    Tsien RW, Fox AP, Hess P, McCleskey EW, Nilius B, Nowycky MC, Rosenberg RL. Multiple types of calcium channel in excitable cells. Soc Gen Physiol Ser 1987;41:167–187.Google Scholar
  2. 2.
    Nayler WG. Calcium antagonists: Whither now? Cardiovasc Drugs Ther 1988;1:617–619.Google Scholar
  3. 3.
    Bush LR, Romson JL, Ash JL, Lucchesi BR. Effect of diltiazem on extent of ultimate myocardial injury resulting from temporary coronary artery occlusion in dogs. J Cardiovasc Pharmacol 1982;4:285–296.Google Scholar
  4. 4.
    Haga Y, Hatori N, Nordlander M, Nordlander R, Sjoquist PO, Ryden L. Coronary venous retroinfusion of felodipine reducing infarct size without affecting regional myocardial blood flow. Eur Heart J 1993;14:1386–1393.Google Scholar
  5. 5.
    Garcia-Dorado D, Theroux P, Fernandez-Aviles F, Elizaga J, Solares J, Galinanes M. Diltiazem and progression of myocardial ischemic damage during coronary artery occlusion and reperfusion in porcine hearts. J Am Coll Cardiol 1987;10:906–911.Google Scholar
  6. 6.
    Hoff PT, Tamura Y, Lucchesi BR. Cardioprotective effects of amlodipine in the ischemic-reperfused heart. Am J Cardiol 1989;64:1011–1061.Google Scholar
  7. 7.
    Roberts R. Review of calcium antagonist trials in acute myocardial infarction. Clin Cardiol 1989;12(Suppl. 3):III41–III47.Google Scholar
  8. 8.
    Ferrari R, Visioli O. Calcium channel blockers and ischaemic heart disease: Theoretical expectations and clinical experience. Eur Heart J 1991;12(Suppl. F):18–24.Google Scholar
  9. 9.
    Landmark K, Abdelnoor M, Kilhovd B, Dorum HP. Infarct size as estimated from peak creatine kinase and lactate dehydrogenase is probably reduced in patients using calcium antagonists at the onset of symptoms. Cardiovasc Drug Ther 1997;11:557–565.Google Scholar
  10. 10.
    Abernethy DR. Pharmacologic and pharmacokinetic profile of miberfradil, a T-and L-type calcium channel antagonist. Am J Cardiol 1997;80(Suppl. 4B):4C–11C.Google Scholar
  11. 11.
    Vander Heide RS, Schwartz LM, Reimer KA. The novel calcium antagonist Ro 40–5967 limits myocardial infarct size in the dog. Cardiovasc Res 1994;28:1526–1532.Google Scholar
  12. 12.
    Richard V, Tron C, Blanc T, Thuillez C. Infarct size limiting properties of Ro 40–5967, a novel non-dihydropyridine calcium channel blocker in anaesthetised rats: Comparisom with verapamil. J Cardiovasc Pharm 1995;25:552–557.Google Scholar
  13. 13.
    Joyeux M, Baxter GF, Thomas DL, Ribuot C, Yellon DM. Protein kinase C is involved in resistance to myocardial infarction induced by heat stress. J Mol Cell Cardiol 1997;29:3311–3319.Google Scholar
  14. 14.
    Bugge E, Ytrehus K. Inhibition of sodium-hydrogen exchange reduces infarct size in the isolated rat heart—a protective additive to ischaemic preconditioning. Cardiovasc Res 1995;29:269–274.Google Scholar
  15. 15.
    Roux S, Buhler M, Clozel JP. Mechanisms of the antiischemic effect of mibefradil, a selective T calcium channel blocker in dogs: Comparison with amlodipine. J Cardiovasc Pharmacol 1996;27:132–139.Google Scholar
  16. 16.
    Clozel JP, Veniant M, Osterrieder W. The structurally novel Ca2+ channel blocker Ro 40–5967, which binds to the [3H] desmethoxyverapamil receptor, is devoid of the negative inotropic effects of verapamil in normal and failing rat hearts. Cardiovasc Drug Ther 1990;4:731–736.Google Scholar
  17. 17.
    Mishra SK, Hermsmeyer K. Selective inhibition of T-type Ca2+ channels by Ro 40–5967. Circ Res 1994;75:144–148.Google Scholar
  18. 18.
    Karila-Cohen D, Dubois-Rande JL, Giudicelli JF, Berdeaux A. Effects of mibefradil on large and small coronary arteries in conscious dogs: Role of vascular endothelium. J Cardiovasc Pharmacol 1996;28:271–277.Google Scholar
  19. 19.
    Nuss HB, Houser SR. T-type Ca2+ current is expressed in hypertrophied adult feline left ventricular myocytes. Circ Res 1993;73:777–782.Google Scholar
  20. 20.
    Garlid KD, Paucek P, Yarov-Yarovny V, et al. Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. Circ Res 1997;81:1072–1082.Google Scholar
  21. 21.
    Liu Y, Sato T, O'Rourke B, Marban E. Mitochondrial ATP-dependent potassium channels: Novel effectors of cardioprotection? Circulation 1998;97:2463–2469.Google Scholar

Copyright information

© Kluwer Academic Publishers 1999

Authors and Affiliations

  • Michaela M. Mocanu
    • 2
  • Shashi Gadgil
    • 1
  • Derek M. Yellon
    • 1
  • Gary F. Baxter
    • 1
  1. 1.Hatter Institute for Cardiovascular StudiesUniversity College Hospital and Medical SchoolLondonUK
  2. 2.Victor Babes InstituteBucharestRomania

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